Small Molecule Degraders of the Hepatitis C Virus Protease Reduce Susceptibility to Resistance Mutations

Targeted protein degradation (TPD) has emerged as a promising new drug development paradigm. We leveraged this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a ‘reversible-covalent’ inhibitor that binds to the hepatitis C virus (HCV) protease active site was conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. We developed an optimized degrader, DGY-08-097, that potently inhibits HCV in a cellular infection model and demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.